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B cell activating factor (BAFF) and T cells cooperate to breach B cell tolerance in lupus-prone New Zealand Black (NZB) mice.

Chang NH, Cheung YH, Loh C, Pau E, Roy V, Cai YC, Wither J - PLoS ONE (2010)

Bottom Line: Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process.In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production.The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help.

View Article: PubMed Central - PubMed

Affiliation: Arthritis Centre of Excellence, Toronto Western Research Institute, Toronto, Ontario, Canada.

ABSTRACT
The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help.

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Elevated BAFF levels in NZB mice enhance survival of transferred NZB dTg B cells.(A) Serum BAFF levels in 6–12 wk old non-Tg (nTg), IgTg and dTg, B6 and NZB mice. (B) Baff mRNA expression in the splenocytes of 8–14 wk old non-Tg (nTg), IgTg and dTg, B6 and NZB mice. Horizontal lines represent the mean for each group examined. Significant p values for the difference between B6 and NZB mice are shown and were determined by one way ANOVA test (Kruskal-Wallis test) followed by Dunns' post test. (C) NZB sHEL recipient mice were injected with TACI-Ig or PBS alone, 1 d before transfer of CFSE-labelled NZB dTg B cells. Splenocytes were analyzed 3 d later by flow cytometry. Numbers indicate the percentage of surviving cells, determined by the ratio of CFSE+ B220+ cells to CFSE+B220- cells as compared to a NZB non-Tg control. Asterisks indicate the significance level for comparison between B6 and NZB mice as determined by the Mann-Whitney test: * p<0.05, ** p<0.005, *** p<0.0005.
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pone-0011691-g004: Elevated BAFF levels in NZB mice enhance survival of transferred NZB dTg B cells.(A) Serum BAFF levels in 6–12 wk old non-Tg (nTg), IgTg and dTg, B6 and NZB mice. (B) Baff mRNA expression in the splenocytes of 8–14 wk old non-Tg (nTg), IgTg and dTg, B6 and NZB mice. Horizontal lines represent the mean for each group examined. Significant p values for the difference between B6 and NZB mice are shown and were determined by one way ANOVA test (Kruskal-Wallis test) followed by Dunns' post test. (C) NZB sHEL recipient mice were injected with TACI-Ig or PBS alone, 1 d before transfer of CFSE-labelled NZB dTg B cells. Splenocytes were analyzed 3 d later by flow cytometry. Numbers indicate the percentage of surviving cells, determined by the ratio of CFSE+ B220+ cells to CFSE+B220- cells as compared to a NZB non-Tg control. Asterisks indicate the significance level for comparison between B6 and NZB mice as determined by the Mann-Whitney test: * p<0.05, ** p<0.005, *** p<0.0005.

Mentions: Since BAFF can rescue anergic self-reactive B cells from deletion by permitting their entry into the follicular and marginal zone B cell compartments [21], [32], we questioned whether NZB mice had elevated levels of BAFF. As shown in Figure 4A, 6–12 wk NZB non-Tg, IgTg, and dTg mice had elevated levels of BAFF as compared to their B6 counterparts. The increased levels of BAFF in NZB IgTg and dTg mice did not result from differences in the number of B cells, as splenic baff RNA expression was also significantly increased (Figure 4B).


B cell activating factor (BAFF) and T cells cooperate to breach B cell tolerance in lupus-prone New Zealand Black (NZB) mice.

Chang NH, Cheung YH, Loh C, Pau E, Roy V, Cai YC, Wither J - PLoS ONE (2010)

Elevated BAFF levels in NZB mice enhance survival of transferred NZB dTg B cells.(A) Serum BAFF levels in 6–12 wk old non-Tg (nTg), IgTg and dTg, B6 and NZB mice. (B) Baff mRNA expression in the splenocytes of 8–14 wk old non-Tg (nTg), IgTg and dTg, B6 and NZB mice. Horizontal lines represent the mean for each group examined. Significant p values for the difference between B6 and NZB mice are shown and were determined by one way ANOVA test (Kruskal-Wallis test) followed by Dunns' post test. (C) NZB sHEL recipient mice were injected with TACI-Ig or PBS alone, 1 d before transfer of CFSE-labelled NZB dTg B cells. Splenocytes were analyzed 3 d later by flow cytometry. Numbers indicate the percentage of surviving cells, determined by the ratio of CFSE+ B220+ cells to CFSE+B220- cells as compared to a NZB non-Tg control. Asterisks indicate the significance level for comparison between B6 and NZB mice as determined by the Mann-Whitney test: * p<0.05, ** p<0.005, *** p<0.0005.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2908288&req=5

pone-0011691-g004: Elevated BAFF levels in NZB mice enhance survival of transferred NZB dTg B cells.(A) Serum BAFF levels in 6–12 wk old non-Tg (nTg), IgTg and dTg, B6 and NZB mice. (B) Baff mRNA expression in the splenocytes of 8–14 wk old non-Tg (nTg), IgTg and dTg, B6 and NZB mice. Horizontal lines represent the mean for each group examined. Significant p values for the difference between B6 and NZB mice are shown and were determined by one way ANOVA test (Kruskal-Wallis test) followed by Dunns' post test. (C) NZB sHEL recipient mice were injected with TACI-Ig or PBS alone, 1 d before transfer of CFSE-labelled NZB dTg B cells. Splenocytes were analyzed 3 d later by flow cytometry. Numbers indicate the percentage of surviving cells, determined by the ratio of CFSE+ B220+ cells to CFSE+B220- cells as compared to a NZB non-Tg control. Asterisks indicate the significance level for comparison between B6 and NZB mice as determined by the Mann-Whitney test: * p<0.05, ** p<0.005, *** p<0.0005.
Mentions: Since BAFF can rescue anergic self-reactive B cells from deletion by permitting their entry into the follicular and marginal zone B cell compartments [21], [32], we questioned whether NZB mice had elevated levels of BAFF. As shown in Figure 4A, 6–12 wk NZB non-Tg, IgTg, and dTg mice had elevated levels of BAFF as compared to their B6 counterparts. The increased levels of BAFF in NZB IgTg and dTg mice did not result from differences in the number of B cells, as splenic baff RNA expression was also significantly increased (Figure 4B).

Bottom Line: Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process.In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production.The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help.

View Article: PubMed Central - PubMed

Affiliation: Arthritis Centre of Excellence, Toronto Western Research Institute, Toronto, Ontario, Canada.

ABSTRACT
The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help.

Show MeSH
Related in: MedlinePlus